With more than one million page views and more than 4,000 items, this blog provides news and commentary on public policy, business and economic issues related to the $3 billion California stem cell agency, officially known as the California Institute for Regenerative Medicine(CIRM). David Jensen, a retired California newsman, has published this blog since January 2005. His email address is djensen@californiastemcellreport.com.

Sunday, February 09, 2014

Here is the text of comments from Jeanne Loring, director of the Center for Regenerative Medicine at the Scripps Research Institute, in response to questions from the California Stem Cell Report concerning the review process for applications in the $40 million stem cell genomics round.

Boldface within Loring's response is hers. Parenthetical identifications of terms or individuals have been inserted in Loring's remarks by the California Stem Cell Report.

California Stem Cell Report: What
questions do you think need to be addressed considering the events
surrounding the award?

Loring:

"1.
What instructions were given to first round applicants about merging
applications?

"Alan (Trounson, CIRM's president) visited all of the first round applicants.
On his visit to San Diego, Alan met separately with me and my
Illumina partners, Larry Goldstein of UCSD and Craig Venter of the
Venter Institute. Alan told me that Larry had taken him to a mens'
club and Craig had taken him to a motorcycle dealership. I took him
for a tour of Illumina's new facilities, which I thought was
appropriate for a scientific site visit.

"At his visit to all of the first round
applicants, Alan Trounson suggested that we merge our applications if
we could. My interpretation of that suggestion was that we actually
merge our center proposals- UCSF's with ours, for example. I was not
told that addition of subcontracts from other institutions could be
interpreted as a merger with those institutions. The Stanford
group's claim that Scripps and Illumina were consortium members of
theirs was disingenuous, since our Scripps/ Illumina consortium was a
competing genome center application, and we did not merge any part of
our application with Stanford's.

"To make the claim that they had 'merged' with Scripps and Illumina, Stanford added one project from a junior
faculty member at Scripps, and contracted Illumina to do sequencing
for them- they have had long-standing contracts with Illumina for
services.

"The difference between Stanford's relationship
with Illumina and my relationship with Illumina is analogous to
Stanford paying a Tesla dealer to repair a car and me teaming up with
Tesla to design a new type of car.

"We
were not told who the other applicants were, which made it a
challenge to determine who we might merge with. We chose to contact
Pui Kwok, through my collaborator Susan Fisher at UCSF, Joe Ecker at
Salk, Mike Snyder at Stanford, and Josh Stuart at UCSC about
potential partnering.

"When
I spoke with one of the people we contacted, he said that I could get
a place in the consortium put together by Stanford if I were to get
my institution to contribute $2 million in matching funds. This was
not entirely a surprise; I had heard from colleagues at UCSD that
UCSD's vice chancellor, David Brenner, had initiated the collection
of matching funds by pledging $2 million to the consortium.

"2.
At the Grants Working Group(GWG, the grant review group): what differences were there between
the stated requirements in the RFA and what the reviewers were told
to do during the meeting?

"Matching funds

"The RFA did NOT require contributions from
grantees, and certainly did not suggest that such contributions would
be considered to be items for the GWG to judge, since they were
tasked with only on the quality of the science, the 'scientific
merit.' To quote from the message sent to me from Gil Sambrano(the CIRM staffer who handles most of the review process),
announcing my score and the GWG report, 'Applications
were reviewed using the criteria detailed in the RFA and scored on
scientific merit.'

"That makes me wonder if the reviewers told at
the GWG meeting to include monetary contributions from the potential
grantees positively in their scoring, in spite of the fact that their
scoring is stated by CIRM as being solely on the basis of scientific
merit?

"During the ICOC (the agency's governing board) meeting, Alan Trounson said
that he had told us during his visit to all of the first round
grantees that it would be important provide money for 'matching' funds. I state unequivocally that he
did not tell me or anyone in my lab about this.

"Scoring applications after removal of projects
that the GWG scored poorly.

"We learned when the reviews were posted
that the GWG scored two of the Stanford center projects very poorly.
We do not know the actual scores they gave those projects, nor do we
know what scores were given to our own projects. We do know that
CIRM instructed the GWG to score the entire Stanford grant after
removing the two low scoring projects. All three of our projects
scored high enough to be included in the overall review of our
application.

"The Stanford project received a range
of scores from 70 to 95 after the two projects were removed. Our
application received a range of scores from 70 to 88 with all
projects left in place. It is not much of a stretch to imagine that
if the low-scoring Stanford projects had been kept in, there would
not have been scores of 95 by any of the reviewers. It is not too
speculative to suggest that their scores would have been lower,
perhaps lower than ours, if the low-scoring projects had not been
removed.
We were not told of the practice of the
GWG altering grants in order to improve the scores of those grants.
I am also appalled that this was done, since it is not allowed in NIH
review of multi project U and P awards, the closest equivalent to the
CIRM genome center award. 'P' awards are Program Project
Grants, in which several investigators write sub-proposals to be done
in concert with each other. I review these grants, and we are
instructed that we cannot remove subprojects in order to change the
scores. Similarly, 'U' awards are for consortia that are
to be coordinately managed. I also review these applications, and
again, it is forbidden for us to alter the applications as written.
The goal of the reviewers for these NIH awards is to 'review the
grant we are given'.CIRM staff indicated at the ICOC meeting that
the GWG had recommended funding of the Stanford project.

This is simply untrue. As the message
from Gil Sambrano states: 'The
GWG understood that this initiative will support only one or two
centers and only a single data coordination and management component
within a total budget of $40M. However, as the GWG's scores and
recommendations were based solely on scientific merit, the group did
not select which center(s) should ultimately be funded as this is a
programmatic assessment.'

The GWG was tasked with scoring based
on 'scientific merit' (which CIRM instructed them would
include monetary contributions). Programmatic assessment is required
to choose an application, and CIRM is not part of the Programmatic
committee, according to the following quote from the message from
Sambrano:'ICOC/Application
Review Subcommittee MeetingFunding
decisions will be made by the Application Review Subcommittee of
CIRM’s governing board, the Independent Citizens Oversight
Committee (ICOC), at a public meeting that will be held in Berkeley,
CA on January 29, 2014. The Subcommittee, which meets
concurrently with the Board, is composed of 16 voting members (the
Patient Advocate and Industry members of the Board, along with the
Chair and statutory Vice Chair of the Board) and 13 non-voting
members (the 13 members of the Board who are appointed from
institutions that are eligible to receive CIRM funding).'The
Applications Review Subcommittee will conduct a programmatic
assessment of applications reviewed by the GWG. The Subcommittee may
consider any factors (such as availability of funds, overall grant
portfolio, RFA priorities, strategic considerations) that might
impact on their decision to fund or not fund applications. The
Subcommittee aims to fund applications that are both scientifically
meritorious and that bring programmatic value to the CIRM portfolio.'

In the meeting, CIRM did not present
information about any application except Stanford's, giving the
strong impression that this application was the only one of merit.
The ICOC members of the Application Review Subcommittee were not
provided with the applications in order to assess the factors they
were charged to assess.

California Stem Cell Report: Are
there structural issues created by Proposition 71, the measure that
created the agency, that made things more or less difficult?

Loring:

"The 29-member
board (ICOC) is difficult enough to deal with, but now that most of the
members are considered to be conflicted and are not allowed to even
discuss the applications, we are left with a small number of
non-scientists making decisions about scientific merit.

"I know that many
members of the ICOC were very upset that they were unable to voice
their opinions about what should be their mission- to guide CIRM's
policies and choices for funding so that they are in the best
interest of the voters."

California Stem Cell Report: Are
there processes at CIRM that show weaknesses or need to be
re-examined? Do
you have any specific recommendations for changes?

Loring:

"The ICOC members
should be provided with all of the grant applications as well as the
reviews. They can choose to ignore them, but if they find that
certain grant apps or disease-specific areas require more high level
consideration, they should have the tools to provide that guidance.

"I am concerned
about the interference of the CIRM president in influencing the ICOC
decisions. He has de facto power to promote or defeat specific
applications, and he often wins by promoting one applicant over
another. Stanford and Stanford faculty-founded companies such as
Stem Cells Inc, are blatantly promoted over others. The relationship
between the president and the head of the stem cell program at
Stanford involves personal favors which make him conflicted and he
should at the very least recuse himself from any discussion or
recommendation of Stanford faculty's applications."

Thank
you for submitting your application under the California Institute
for Regenerative Medicine’s (CIRM) Stem Cell Genomics Centers of
Excellence Awards RFA 12-06. We are providing you this report as the
Program Director (PD) and designated point of contact on the
application, but it is your responsibility to share this information
as appropriate with members of your team.

The
applications underwent peer review at a meeting held on November 7-8,
2013 by the members of CIRM’s Grants Working Group (GWG).
Applications were reviewed using the criteria detailed in the RFA and
scored on scientific merit.

Review
ReportBelow,
please find the Review Report of your application. This report
includes the average scientific score and the funding recommendation
of the GWG. Applications are scored on a scale that ranges from 1 –
100, with 100 being the highest achievable score.

Applications
are separated into three funding tiers. An application’s
average score determines the funding tier as follows:

The
Review Report provides only a brief summary of the evaluation of your
application by the GWG. The report is not an exhaustive critique and
does not cover all of the factors that may have contributed to the
final score or the final recommendation. The report highlights key
points relevant to the review criteria that were captured from
reviewers’ written comments and from the discussion of your
proposal by the GWG during the review meeting.

ICOC/Application
Review Subcommittee MeetingFunding
decisions will be made by the Application Review Subcommittee of
CIRM’s governing board, the Independent Citizens Oversight
Committee (ICOC), at a public meeting that will be held in Berkeley,
CA on January 29, 2014. The Subcommittee, which meets
concurrently with the Board, is composed of 16 voting members (the
Patient Advocate and Industry members of the Board, along with the
Chair and statutory Vice Chair of the Board) and 13 non-voting
members (the 13 members of the Board who are appointed from
institutions that are eligible to receive CIRM funding).

The
Applications Review Subcommittee will conduct a programmatic
assessment of applications reviewed by the GWG. The Subcommittee may
consider any factors (such as availability of funds, overall grant
portfolio, RFA priorities, strategic considerations) that might
impact on their decision to fund or not fund applications. The
Subcommittee aims to fund applications that are both scientifically
meritorious and that bring programmatic value to the CIRM portfolio.

Under
California’s open meeting laws, members of the public, including
applicants for CIRM funding, may provide written and oral comments to
the ICOC regarding items on the Board’s agenda. Applicants may
attend and observe the ICOC meeting. Applicants may contribute oral
comments for not more than three (3) minutes during the public
comment periods. The ICOC Chairman will announce the public comment
period, which typically occurs prior to the Board’s voting on any
motion. Applicants may also provide written comments to the ICOC. All
correspondence to the ICOC must be submitted to the Executive
Director of the ICOC, Maria Bonneville, at mbonneville@cirm.ca.gov.
Please do not send correspondence to the ICOC that relates to an
appeal of a funding recommendation by the GWG as it will be
redirected to the CIRM Review Office (see “Response to Review”
below).

In
preparation for the ICOC meeting, the Review Report (with PI and
institution identities removed) will be posted no later than Friday,
January 17, 2014 on our website
at http://www.cirm.ca.gov/ReviewReports.
Additional information for CIRM’s public meetings can also be found
on our website.

Award
NotificationCIRM
will notify you by email of the ICOC’s funding decisions following
the ICOC meeting.

Response
to ReviewThe
GWG conducts the scientific evaluation of proposals submitted to
CIRM. If the applicant (PI/PD) wishes to appeal the scientific review
by the GWG (or seek reconsideration of the recommendation), the PI/PD
must first consult with the CIRM Review Office. All appeal requests
must be made through the CIRM Review Office within 10 days of CIRM
making this report available (i.e., deadline is January 21, 2014).
Grounds for an appeal are limited to the circumstances described in
“Guidance for Appeal of Scientific Review and Reconsideration
Policy” available via this
link: http://www.cirm.ca.gov/board-and-meetings/guidance-appeals-and-requests-reconsideration-grants-working-group-funding--Gilberto
R. Sambrano, Ph.D.Associate
Director, ReviewCalifornia
Institute for Regenerative Medicine210
King StreetSan
Francisco, CA 94107(415)
396-9103To:
jloring@scripps.edu;
wynne@scripps.eduREVIEW
REPORT FOR CIRM RFA 12-06R GENOMICS CENTERS OF EXCELLENCE AWARDS (R)Application:
Center for
Advanced Stem Cell Genomics

PI:
Jeanne
LoringInstitution:
Scripps
Research Institute

Recommendation
Overview: The
GWG provided two final scores for each application as follows: 1) an
overall center score (covering the center-initiated projects,
collaborative research activities, and center organization and
operations plan) and 2) a data coordination and management component
score.The
overall scientific merit and quality of the proposals submitted under
this RFA were viewed by the GWG to be deserving of high scores.
Overall center scores placed four proposals in Tier 1, one proposal
in Tier 2 and none in Tier3. The separate data management and
coordination component scores placed two proposals in Tier 1, two in
Tier 2 and one in Tier 3.The
GWG understood that this initiative will support only one or two
centers and only a single data coordination and management component
within a total budget of $40M. However, as the GWG's scores and
recommendations were based solely on scientific merit, the group did
not select which center(s) should ultimately be funded as this is a
programmatic assessment. CIRM staff is recommending that the ICOC
fund only the highest scoring genomics center and the corresponding
highest data coordination and management center which together will
fulfill the goals of this initiative.The
scores, GWG Tier recommendation and CIRM staff recommendation are as
follows:

GWG
Overall Center Recommendation: Tier 1GWG
Overall Final Score: 76

GWG
Data Center Recommendation: Tier 2GWG
Data Center Final Score: 72CIRM
Staff Recommendation: Do not fundEXECUTIVE
SUMMARYThis
Genomics Center will be led by a program director (PD) from an
academic institution and a co-PD from an industry organization. Three
Center-Initiated Projects (CIPs) are proposed, and, as required by
the RFA, a plan for inclusion of Collaborative Research Projects and
a Data Coordination and Management Center are described.

Center
Organization and Operational Plan -
The organization of the proposed Genomics Center is well conceived as
a collaboration between highly qualified investigators from an
academic institution and an industry partner, representing a
diversity of competencies. The balance between expertise in stem cell
biology and genomics technologies is a particular strength.

-
The PD has extensive research experience at the interface of stem
cell biology and genomics and is committed to serving the stem cell
community; he/she is well suited to lead this program.

-
The industry partner institution, and especially the co-PD, is well
positioned to develop novel cutting edge genomics technologies and
make them accessible to customers.-
The teams from the two applicant institutions have a
well-established, strong working relationship; reviewers considered
this an important attribute of this proposal.

-
All elements necessary for the establishment and operation of a
successful Genomics Center are in place; the structure and
composition of the proposed administrative and oversight committees
are appropriate and should ensure both delivery of projects and high
standards of work.

-
The three CIPs are designed to support the service aspects of this
Genomics Center by focusing on the development of tools that can be
generally used to explore genomics data. Reviewers considered it a
strength that, if successful, these projects will both create novel
tools and technologies and validate them. There was some concern that
some of the tools may not be made easily and widely available.

-
Although a letter from leadership indicates enthusiastic
institutional support from the academic institution, no additional
funds or specific dedicated space have been designated. Reviewers
expressed serious concern about this lack of material commitment.

-
Some reviewers expressed concern that both the PD and co-PD are
already heavily committed individuals and questioned whether they
would have the capacity to fully provide a strong commitment to this
project.

Center
Organization and Operational Plan -
The proposed Genomics Center appears well designed to support
collaborative research projects and to make relevant state-of-the-art
genomics technologies readily accessible to investigators with
primary expertise in stem cell biology or translational research.

-
The proposed application process is appropriate, review procedures
and criteria are well thought out.

-
The offer to culture cells for external collaborators in the Genomics
Center's core lab is especially appealing, as that would remove a
variable from the experiments and thus help with standardization of
conditions for genomics assays.

-
Concern was expressed about whether potential collaborators who have
limited experience in genomics would receive adequate assistance in
designing their proposed studies.

CIP-1The
applicants propose to develop an updated and expanded version of an
existing genomics tool. They plan to make available global gene
expression and epigenomic data, obtained through a series of
systematic analyses of human pluripotent stem cells and their
derivatives, to serve as reference for future experiments. They also
propose to analyze the heterogeneity of stem cell populations and to
develop genomic tools for the assessment of stem cell quality.
Finally, they intend to use disease-specific induced pluripotent stem
cells (iPSC) to study the molecular basis of two neurodevelopmental
diseases and identify disease-modifying compounds.

-
This project adopts a broad approach toward developing pragmatic,
accessible tools for basic research on stem cells in vitro, and to
lay the groundwork for more effective clinical translation. This
would represent a valuable resource to the stem cell community.

-
Enthusiasm was diminished by the notion that most of the activities
are applications of existing tools or extensions of existing work.
While important goals, the activities were not viewed as particularly
innovative.

-
The goals of this project are overly ambitious, raising doubt that
all aims can be achieved. Given the tremendous track record of the
principal investigator (PI), though, it is expected that substantial
progress will be made.

-
Reviewers' opinions about the utility of an already existing
analytical tool, to be further developed under this award, were
divided. Some judged it positively as an important tool that has been
made freely available in its current form and were enthusiastic about
the plan for dissemination of the updated version. Conceptually, they
considered the proposed approach to be very valuable, as it has the
potential to provide objective standards for assessing cell fate and
for quality control of cell populations. Other reviewers expressed
concern that the current tool has not been widely adopted in the stem
cell community, calling into question its usefulness.-
The proposed work on neurodevelopmental diseases is disconnected from
the central focus of this project and might have been better
developed as a separate project.-
Reviewers criticized the general lack of experimental detail,
particularly in aims 4 and 5, which impeded assessment of
feasibility.-
The project plays to the strengths of the PI as a well-established
leader in the stem cell field with a strong record of productivity
and innovation.

-
The broad scope of the project is matched by the experience and
expertise of the team involved.

CIP-2This
project addresses the integrity of stem cells for clinical
transplantations and their utility in translational and clinical
research. The goals are to establish informatics tools for
determining the functional significance of genome wide molecular
variations in therapeutic stem cell populations and to develop and
validate methods for assessing the prevalence of deleterious
alterations in stem cell populations. The applicants also plan to
develop and validate a workflow for integrating genomics information
with identification of potential therapeutic compounds and their
effects on patient-derived induced pluripotent stem cells and on
patient treatment outcomes. Finally, the plan is to disseminate all
developed tools and protocols to the stem cell community.

-
The utility of the proposed tools and protocols for translational
genomics-based research would be high.-
The first goal is straightforward and feasible. Reviewers emphasized
that input data must be high quality, as noted by the applicants, and
suggested that applicants consider that the cellular differentiation
state may affect functional significance of specific genomics
variation.

-
Other goals are more risky, but if successfully developed, they
should be widely applicable and help stimulate the use of stem
cell-based systems to explore both disease mechanisms and potential
therapies.-
Toward assessing prevalence of deleterious alterations in stem cell
populations, reviewers recommended that a variety of additional stem
cell datasets, especially some originating outside the team, be
included in the project.

-
The feasibility of a key component of the study, linking genomic
information from patients to potential therapeutics and
individualized treatments, was difficult to assess, since the
applicants did not specify the types of diseases to be studied.-
Reviewers observed that parts of this proposal are vague and hard to
follow, and it was unclear what some of the deliverables would be.

-
There is a clear plan for dissemination of the acquired expertise and
knowledge.

-
The PI is well qualified for this work and has assembled a powerful
leadership team that possesses the necessary expertise.

CIP-3This
project is led by the industry partner organization and is focused on
the development of several single cell genomic technologies and tools
for large-scale epigenetic analyses.

-
Reviewers noted that only one of the technologies under development
is truly stem cell-specific, but the proposed work would nevertheless
deliver technologies extremely valuable to the stem cell community.

-
The tools to be improved or developed are at the forefront of
technical advances.

-
Reviewers geatly appreciated the novelty of one of the proposed
technologies.-
Some reviewers were concerned that the project essentially
constitutes commercial development of genomic products and questioned
whether it was appropriate for CIRM to support this activity.
Others felt that the developed technologies would provide valuable
research tools and could have great potential impact on stem cell
science.-
Concern was expressed about whether the new technologies would be
specifically disseminated to California investigators and whether
their cost might be prohibitive to many researchers.

-
The basic technologies underlying this proposal have already been
developed and it should therefore be feasible to complete the
proposed developments in the proposed time scale.

-
The PI and team are exceptionally well qualified to deliver on this
project.

Data
Coordination and Management -
The DCM team is led by two individuals. One has a track record of
developing a highly successful, adaptable, user-friendly platform.
The other is an expert in medical informatics, although reviewers
expressed concern that a biosketch for this individual was not
included in the proposal.

-The
proposed DCM structure and leadership would likely ensure solid
database structure, data access and visualization capabilities.-
Reviewers considered the details provided on the data management plan
to be inadequate; there was little description of how the DCM Center
will participate in data integration and analysis or interact with
various projects.

-
Reviewers acknowledged the importance of patient privacy protection
but felt the focus on this issue in the application was
overemphasized and distracting.

-
The descriptions of data visualization tools are reasonable but not
particularly innovative or tailored to the specific needs of the stem
cell community."

About Me

The California Stem Cell Report is the only nongovernmental website devoted solely to the $3 billion California stem cell agency. The report is published by David Jensen, who worked for 22 years for The Sacramento Bee in a variety of editing positions, including executive business editor and special projects editor. He was the primary editor on the 1992 Pulitzer Prize-winning series, "The Monkey Wars" by Deborah Blum, which dealt with opposition to research on primates. Jensen served as a press aide in the 1974 campaign and first administration of Gov. Jerry Brown. (Time served: two years and one week.) He writes from his sailboat on the west coast of Mexico with occasional visits to land. Jensen began writing about the stem cell agency in 2005, noting that it is an unprecedented effort that uniquely combines big science, big business, big academia, big politics, religion, ethics and morality as well as life and death. The California Stem Cell Report has been identified as one of the best stem cell sites on the Internet. Its readership includes the media (both mainstream and science), a wide range of academic/research institutions globally, the NIH and California policy makers.